Chronic pain is a major contributor to disability and is the cause of much suffering. The successful treatment of severe and chronic pain is a primary goal of the physician, with opioid analgesics being preferred drugs for doing so.
Three major classes of opioid receptors in the central nervous system (CNS) have long been known, with each class having subtype receptors. These receptor classes are known as μ, κ and δ. As opiates have a high affinity for these receptors while not being endogenous to the body, research followed in order to identify and isolate the endogenous ligands to these receptors. These ligands were identified as endorphins, dynorphins and enkephalins, respectively.
Experimentation eventually led to the identification of an opioid receptor-like (ORL-1) receptor with a high degree of homology to the known receptor classes. The ORL-1 receptor was classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology. It was initially demonstrated that non-selective ligands having a high affinity for μ, κ and δ receptors had low affinity for the ORL-1 receptor. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the term “orphan receptor.” See, e.g., Henderson et al., “The orphan opioid receptor and its endogenous ligand-nociceptin/orphanin FQ,” Trends Pharmacol. Sci. 18(8):293-300 (1997).
Subsequent research led to the isolation and structure of the endogenous ligand of the ORL-1 receptor (i.e., nociceptin; also known as orphanin FQ (OFQ)). This ligand is a seventeen amino acid peptide structurally similar to members of the opioid peptide family.
The discovery of the ORL-1 receptor presents an opportunity in drug discovery for novel compounds that can be administered for pain management or other syndromes modulated by this receptor.
U.S. Pat. Nos. 6,872,733, 7,456,198, 7,495,109, and 7,678,809 disclose benzoimidazolones or derivatives thereof as compounds having affinity for the ORL-1 receptor.
U.S. Pat. No. 6,867,222 and U.S. Pat. App. Pub. No. 2008/0214827 disclose cyanoimino-benzoimidazoles or derivatives thereof, and methods for making the same, as compounds for modulating the pharmacodynamic response from the ORL-1 receptor.
U.S. Pat. No. 7,939,670 discloses benzooxazolones or derivatives thereof as compounds for modulating the pharmacodynamic response from the ORL-1 receptor.
U.S. Pat. App. No. 2010/0144591 describes benzoimidazole derivatives and methods of using the same to treat or prevent pain.
U.S. Pat. No. 7,105,505 discloses benzoimidazole derivatives useful as histamine H3 antagonists.
U.S. Pat. Nos. 6,172,067, 6,340,681, and 6,861,425 disclose certain piperidyl benzoimidazole compounds as ORL-1 receptor agonists.
U.S. Pat. App. Nos. 2003/0119869 and 2010/001007 describe certain benzoimidazole compounds or piperidine derivatives, respectively, as chemokine receptor CCR5 modulators.
U.S. Pat. App. No. 2008/0287479 describes certain benzimidazol-2-one compounds useful in the inhibition or modulation of serene palmitoyl transferase.
International PCT Publication No. WO 2004/069828 describes certain piperidine compounds as therapeutic agents for schizophrenia.
International PCT Publication Nos. WO 99/46260, WO 99/50254, WO 01/90102, WO 2005/028451, WO 2003/062234, and U.S. Pat. App. No. 2005/0256000, respectively, describe quinoxalines or derivatives thereof as (i) inhibitors of protein kinase C, (ii) serine protease inhibitors, (iii) herbicides, (iv) M2 acetylcholine receptor agonists, (v) medicaments for diseases involving poly(ADP-ribose) polymerase, and (vi) safeners for plants.
Hayashi et al. (“Discovery of 1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole: Integrated Thug-Design and Structure-Activity Relationships for Orally Potent, Metabolically Stable and Potential-Risk Reduced Novel Non-Peptide Nociceptin/Orphanin FQ Receptor Agonist as Antianxiety Drug,” Chem. Biol. Drug Des. 74:369-381 (2009) and “Novel Non-Peptide Nociceptin/Orphanin FQ Receptor Agonist, 1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole: Design, Synthesis, and Structure-Activity Relationship of Oral Receptor Occupancy in the Brain for Orally Potent Antianxiety Drug,” J. Med. Chem. 52:610-625 (2009)) disclose substituted 1-(1-(1-methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3-yl)-1H-benzo[d]imidazoles said to be in vitro non-peptide full ORL-1 receptor agonists and oral anxiolytics in mice.
Hayashi et al., “Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: Design, synthesis, and structure-activity relationships,” Bioorg. Med. Chem. 18:7675-7699 (2010), disclose substituted 1-(1-cyclooctylpiperidin-4-yl)-2-(piperazin-1-yl)-1H-benzo[d]imidazoles said to be non-peptide ORL-1 receptor agonists and provide an inhibitory effect against mechanical allodynia in rats.
Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.